Dabifor

INSTRUCTION for medical use of the medicinal product Dabifor® (Dabifor)

Composition:

Active substance: dabigatran etexilate;

1 capsule contains: dabigatran etexilate mesilate – 126.83 mg, equivalent to dabigatran etexilate – 110 mg;

Excipients: microcrystalline cellulose (E 460), sodium croscarmellose (E 468), crospovidone, talc (E 553b), tartaric acid granules, hydroxypropylcellulose, mannitol (E 421), magnesium stearate (E 572);

capsule shell composition: hypromellose (E 464), titanium dioxide (E 171), iron oxide red (E 172);

printing on the capsule with black ink***;

***ink composition: black ink (shellac (E 904), propylene glycol (E 1520), concentrated ammonia solution (E 527), potassium hydroxide (E 525), iron oxide black (E 172)).

Dosage form. Hard capsules.

Main physicochemical characteristics: size “0” capsule, pink/opaque pink cap and body with the marking “DA110” printed in black ink.

Pharmacotherapeutic group. Antithrombotic agents. Direct thrombin inhibitors.

ATC code B01A E07.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Dabigatran etexilate belongs to low-molecular-weight prodrugs which do not exhibit pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted into dabigatran via esterase-catalyzed hydrolysis in blood plasma and liver. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and the main active substance in blood plasma.

Since thrombin (a serine protease) mediates the conversion of fibrinogen to fibrin in the coagulation system, its inhibition prevents thrombus formation. Dabigatran inhibits free thrombin, fibrin-bound thrombin, and thrombin-induced platelet aggregation.

Pharmacodynamic effects. There is a clear correlation between plasma concentration of dabigatran and the degree of anticoagulant effect based on phase II studies. Dabigatran prolongs thrombin time (TT), clotting time (CT), and activated partial thromboplastin time (aPTT).

A calibrated diluted thrombin time (dTT) assay provides an approximate value of dabigatran plasma concentration that can be compared with expected levels. If the result of the calibrated dTT test is at or below the lower limit of quantification, additional coagulation tests (TT, CT, and aPTT) should be considered.

Clotting time (CT) may provide a direct measurement of the activity of direct thrombin inhibitors.

The aPTT test is widely available and provides an approximate indicator of anticoagulant intensity achieved with dabigatran. However, the aPTT test has limited sensitivity and is not used for precise quantitative assessment of anticoagulant effect, especially at high plasma concentrations of dabigatran. Although high aPTT values should be interpreted with caution, they indicate the presence of anticoagulant effect in the patient.

Clinical efficacy and safety. In the RE-LY clinical trial, dabigatran etexilate at a dose of 110 mg twice daily was non-inferior to warfarin in preventing stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with a reduced risk of intracranial hemorrhage, overall bleeding, or major bleeding. The 150 mg twice-daily dose of dabigatran significantly reduced the risk of ischemic and hemorrhagic stroke, cardiovascular mortality, intracranial hemorrhage, and overall bleeding compared to warfarin. The rate of major bleeding with these doses was comparable to that observed with warfarin. The incidence of myocardial infarction with dabigatran etexilate at doses of 110 mg and 150 mg twice daily was not significantly increased compared to warfarin (risk ratio [RR] 1.29; p = 0.0929 and RR 1.27; p = 0.1240, respectively). A significant positive impact of dabigatran etexilate compared to warfarin is improved monitoring of the international normalized ratio (INR).

Non-interventional study data. In a non-interventional study (GLORIA-AF), safety and efficacy data were prospectively collected (during phase II) in patients with newly diagnosed NVAF receiving dabigatran etexilate under real-world conditions. The study included 4,859 patients (55 % received 150 mg twice daily, 43 % received 110 mg twice daily, and 2 % received 75 mg twice daily). Patients were followed for 2 years. Mean CHADS2 and HAS-BLED scores were 1.9 and 1.2, respectively. The mean treatment observation period was 18.3 months. Major bleeding occurred at a rate of 0.97 events per 100 patient-years. Life-threatening bleeding was recorded at 0.46 events per 100 patient-years, intracranial hemorrhage at 0.17 events per 100 patient-years, and gastrointestinal bleeding at 0.60 events per 100 patient-years. Stroke occurred at a rate of 0.65 events per 100 patient-years.

Additionally, in a non-interventional study [Graham DJ et al., Circulation. 2015;131:157–164] involving over 134,000 elderly patients with NVAF in the United States (equivalent to more than 37,500 patient-years of treatment observation), dabigatran etexilate (84 % of patients receiving 150 mg twice daily, 16 % receiving 75 mg twice daily) was associated with reduced risk of ischemic stroke (RR 0.80; 95 % confidence interval [CI] 0.67–0.96), intracranial hemorrhage (RR 0.34; CI 0.26–0.46), and mortality (RR 0.86; CI 0.77–0.96), as well as an increased risk of gastrointestinal bleeding (RR 1.28; CI 1.14–1.44) compared to warfarin. No difference was observed in the risk of major bleeding (RR 0.97; CI 0.88–1.07).

These real-world observations are consistent with the established safety and efficacy profile of dabigatran etexilate demonstrated in the RE-LY trial when used for the approved indication.

Patients undergoing percutaneous coronary intervention (PCI) with stenting. A prospective, randomized, open-label study with blinded endpoint assessment (PROBE design, phase IIIb) evaluated dual therapy with dabigatran etexilate (110 mg or 150 mg twice daily) plus clopidogrel or ticagrelor (P2Y12 antagonist) versus triple therapy with warfarin (dosed to achieve INR 2.0–3.0) plus clopidogrel or ticagrelor and acetylsalicylic acid (ASA). The study included 2,725 NVAF patients who underwent PCI with stenting (RE-DUAL PCI). Patients were randomized to dual therapy with dabigatran etexilate 110 mg twice daily, dual therapy with dabigatran etexilate 150 mg twice daily, or triple therapy with warfarin. Elderly patients outside the United States (aged ≥80 years in all countries and ≥70 years in Japan) were randomized to receive dual therapy with dabigatran etexilate 110 mg or warfarin-based therapy. The primary endpoint was a composite of major bleeding based on ISTH (International Society on Thrombosis and Haemostasis) criteria or clinically relevant non-major bleeding.

The rate of the primary endpoint was 15.4 % (151 patients) in the dual therapy group with dabigatran etexilate 110 mg twice daily versus 26.9 % (264 patients) in the warfarin triple therapy group (RR 0.52; 95 % CI 0.42, 0.63; p < 0.0001 for non-inferiority and p < 0.0001 for superiority) and 20.2 % (154 patients) in the dual therapy group with dabigatran etexilate 150 mg twice daily versus 25.7 % (196 patients) in the corresponding warfarin triple therapy group (RR 0.72; 95 % CI 0.58, 0.88; p < 0.0001 for non-inferiority and p = 0.002 for superiority). In descriptive analyses, the rate of major bleeding according to TIMI (Thrombolysis in Myocardial Infarction) criteria was lower in both dabigatran dual therapy groups compared to the warfarin triple therapy group: 14 events (1.4 %) in the 110 mg group versus 37 events (3.8 %) in the warfarin group (RR 0.37; 95 % CI 0.20, 0.68; p = 0.002) and 16 events (2.1 %) in the 150 mg group versus 30 events (3.9 %) in the corresponding warfarin group (RR 0.51; 95 % CI 0.28, 0.93; p = 0.03). Both dabigatran dual therapy groups showed lower rates of intracranial hemorrhage compared to the corresponding warfarin triple therapy group: 3 events (0.3 %) in the 110 mg group versus 10 events (1.0 %) in the warfarin group (RR 0.30; 95 % CI 0.08, 1.07; p = 0.06) and 1 event (0.1 %) in the 150 mg group versus 8 events (1.0 %) in the corresponding warfarin group (RR 0.12; 95 % CI 0.02, 0.98; p = 0.047). Regarding the composite efficacy endpoint of death, thromboembolic events (myocardial infarction, stroke, and systemic embolism), or unplanned revascularization, both dabigatran dual therapy groups collectively were non-inferior to the warfarin triple therapy group (13.7 % vs. 13.4 %; RR 1.04; 95 % CI 0.84, 1.29; p = 0.0047 for non-inferiority). No statistically significant differences were observed in individual components of the efficacy endpoints between either dabigatran dual therapy group and the warfarin triple therapy group.

Clinical studies on thromboembolism prevention in patients with mechanical heart valves. Clinical trials in patients who recently underwent mechanical heart valve replacement surgery (e.g., during hospitalization) and in patients who underwent mechanical heart valve replacement more than 3 months prior showed an increased risk of thromboembolic complications (primarily stroke and prosthetic valve thrombosis, symptomatic and/or asymptomatic) and higher rates of bleeding with dabigatran etexilate compared to warfarin. In patients during the early postoperative period, major bleeding primarily manifested as hemorrhagic pericardial effusion, especially in patients who initiated dabigatran etexilate (e.g., on day 3) after heart valve replacement surgery (see section "Contraindications").

Pharmacokinetics.

After oral administration, dabigatran etexilate is rapidly and completely converted into dabigatran, the active form in plasma. The conversion of the prodrug dabigatran etexilate into the active substance dabigatran via esterase-catalyzed hydrolysis is the dominant metabolic reaction. The absolute bioavailability of dabigatran after oral administration of dabigatran etexilate is approximately 6.5 %.

After oral administration of dabigatran etexilate, the pharmacokinetic profile of dabigatran in plasma is characterized by a rapid increase in concentration, reaching maximum concentration (Cmax) within 0.5–2 hours after administration.

Absorption. Postoperative absorption of dabigatran etexilate, assessed 1–3 hours after surgery, was relatively low compared to absorption in healthy volunteers and showed a similar area under the plasma concentration-time curve (AUC) without high Cmax. Cmax in plasma is reached 6 hours after administration in the postoperative period due to concomitant factors such as anesthesia, gastrointestinal paresis, and surgical intervention, regardless of the oral dosage form. Additional studies showed that delayed and slowed absorption typically occurs only on the day of surgery. In subsequent days, absorption of dabigatran is rapid, with Cmax in plasma achieved within 2 hours after drug administration.

Food does not affect the bioavailability of dabigatran etexilate but delays the time to reach maximum plasma concentration (Tmax) by 2 hours. Cmax and AUC are dose-proportional.

Bioavailability after oral administration may be increased by 75 % after a single dose and by 37 % at steady state compared to the capsule formulation when pellets are administered without hydroxypropylmethylcellulose in the capsule coating. Therefore, the integrity of the hydroxypropylmethylcellulose capsule coating must always be maintained during clinical use to prevent unintentional increases in dabigatran etexilate bioavailability (see section "Dosage and administration").

Distribution. Low (34–35 %), concentration-independent plasma protein binding of dabigatran in human plasma has been observed. The volume of distribution of dabigatran (60–70 L) exceeds total body water volume, indicating moderate tissue distribution.

Metabolism. The metabolism and excretion of dabigatran were studied after administration of a single intravenous dose of radiolabeled dabigatran to healthy male volunteers. After intravenous administration, radiolabeled dabigatran was primarily excreted in urine (85 %). Fecal excretion accounted for 6 % of the administered dose. Recovery of total radioactivity reached 88–94 % within 168 hours after dabigatran administration. Dabigatran undergoes conjugation to form pharmacologically active acylglucuronides. There are four positional isomers (1-O-, 2-O-, 3-O-, 4-O-acylglucuronide), each constituting less than 10 % of total dabigatran in plasma. Traces of other metabolites could only be detected using highly sensitive analytical methods. Dabigatran is primarily excreted unchanged in urine at a rate of approximately 100 mL/min, corresponding to glomerular filtration rate.

Excretion. Plasma concentration of dabigatran decreases biexponentially, with a mean terminal half-life of 11 hours in healthy elderly volunteers. After multiple doses, the terminal half-life is approximately 12–14 hours. The half-life is independent of dose. The half-life is prolonged in patients with impaired renal function.

Special patient populations

Renal impairment. In phase I studies, AUC of dabigatran after oral administration was approximately 2.7-fold higher in adult volunteers with moderate renal impairment (creatinine clearance (CrCl) 30–50 mL/min) compared to those with normal renal function.

In a small number of adult volunteers with severe renal impairment (CrCl 10–30 mL/min), AUC of dabigatran was approximately 6-fold higher and the half-life approximately 2-fold longer compared to those with normal renal function (see sections "Contraindications", "Special precautions", and "Dosage and administration").

Half-life of dabigatran depending on renal function (glomerular filtration rate

(CrCl) - half-life, hours (gCV %; range): ≥ 80 mL/min – 13.4 (25.7 %; 11.0–21.6); ≥ 50–< 80 mL/min – 15.3 (42.7 %; 11.7–34.1); ≥ 30–< 50 mL/min – 18.4 (18.5 %; 13.3–23.0); < 30 mL/min – 27.2 (15.3 %; 21.6–35.0).

Additionally, exposure to dabigatran (trough and peak levels) was evaluated in a prospective, open-label, randomized pharmacokinetic study in patients with NVAF and severe renal impairment (CrCl 15–30 mL/min) receiving dabigatran etexilate 75 mg twice daily.

With this dosing regimen, the geometric mean trough concentration, measured immediately before the next dose, was 155 ng/mL (gCV 76.9 %), and the geometric mean peak concentration, measured 2 hours after the last dose, was 202 ng/mL (gCV 70.6 %).

Dabigatran clearance during hemodialysis was studied in 7 adult patients with end-stage renal disease without atrial fibrillation. Dialysis was performed with dialysate flow rate of 700 mL/min for 4 hours and blood flow rate of either 200 mL/min or 350–390 mL/min. This resulted in a 50 % and up to 60 % reduction in dabigatran concentration, respectively. The amount of substance removed by dialysis is proportional to a blood flow rate of 300 mL/min. Anticoagulant activity of dabigatran decreases with decreasing plasma concentration. The procedure did not affect the pharmacokinetic/pharmacodynamic relationship.

Elderly patients. In a phase I dedicated pharmacokinetic study in elderly patients, AUC increased by 40–60 % and Cmax by more than 25 % compared to younger patients. The effect of age on dabigatran distribution was confirmed in the RE-LY study: approximately 31 % higher concentration in patients ≥75 years and approximately 22 % lower concentration in patients <65 years compared to patients aged 65–75 years (see sections "Special precautions" and "Dosage and administration").

Hepatic impairment. No changes in dabigatran distribution were observed in 12 adult patients with moderate hepatic impairment (Child-Pugh class B) compared to 12 control patients (see sections "Special precautions" and "Dosage and administration").

Body weight. Dabigatran concentration was approximately 20 % lower in adult patients with body weight >100 kg compared to those with body weight 50–100 kg. The majority (80.8 %) of volunteers were in the category ≥50 kg and <100 kg, with no clear difference in dabigatran concentration (see sections "Special precautions" and "Dosage and administration"). Data for adult patients with body weight <50 kg are limited.

Sex. Exposure to the active substance in venous thromboembolism prevention studies was 40–50 % higher in female patients; dose adjustment is not recommended. Female patients with atrial fibrillation had on average 30 % higher concentrations during and after treatment. Dose adjustment is not recommended (see section "Dosage and administration").

Race. There are no clinically significant inter-ethnic differences in the pharmacokinetics and pharmacodynamics of dabigatran in patients of Caucasian, African, Latino, Japanese, or Chinese origin.

Pharmacokinetic interactions. In vitro interaction studies did not show inhibition or induction of major cytochrome P450 isoenzymes. This was confirmed by in vitro studies in healthy volunteers, in which no interactions were observed between dabigatran and active substances such as atorvastatin (CYP3A4), digoxin (P-gp transporter interaction), or diclofenac (CYP2C9).

Clinical characteristics.

Indications.

Primary prevention of venous thromboembolic complications in adult patients who have undergone major orthopedic surgery of hip or knee replacement.

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF) with one or more risk factors such as: prior stroke or transient ischemic attack (TIA), age ≥ 75 years, heart failure (New York Heart Association [NYHA] class ≥ II), diabetes mellitus, or arterial hypertension.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.

Contraindications.

• Known hypersensitivity to dabigatran or dabigatran etexilate, or to any of the excipients of the medicinal product (see section "Composition").
• Severe renal impairment (CrCl < 30 mL/min).
• Active clinically significant bleeding.
• Injury or condition considered a significant risk factor for major bleeding, including current or recent gastrointestinal ulceration, presence of malignant tumors with high bleeding risk, recent injury to brain or spinal cord, spinal or ophthalmologic surgery, recent intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or significant intraspinal or intracerebral vascular abnormalities.
• Concomitant use of any anticoagulant medicinal product such as unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin), heparin derivatives (fondaparinux), oral anticoagulants (warfarin, rivaroxaban, apixaban), except under specific conditions such as transitioning from or to anticoagulant therapy (see section "Dosage and administration"), when UFH is used at doses required to maintain patency of a central venous or arterial catheter, or when UFH is used during catheter ablation for atrial fibrillation (see section "Interaction with other medicinal products and other forms of interaction").
• Hepatic impairment or liver disease that may affect survival.
• Concomitant use of strong P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole, dronedarone, and the fixed-dose combination glecaprevir/pibrentasvir (see section "Interaction with other medicinal products and other forms of interaction").
• Mechanical heart valve requiring anticoagulant therapy (see section "Pharmacological properties" ("Pharmacodynamics")).

Interaction with other medicinal products and other forms of interaction.

Transporter interactions

Dabigatran etexilate is a substrate of the efflux transporter P-gp. Concomitant use of P-gp inhibitors is expected to increase plasma concentrations of dabigatran. Unless otherwise specified, careful clinical monitoring (for signs of bleeding or anemia) is recommended when dabigatran is used concomitantly with strong P-gp inhibitors. Dose reduction of dabigatran may be required when used in combination with certain P-gp inhibitors (see sections "Pharmacodynamics", "Contraindications", "Special warnings and precautions for use", and "Dosage and administration").

P-gp inhibitors

Concomitant use contraindicated (see section "Contraindications")

Ketoconazole. Ketoconazole increases the total AUC_0–∞ and C_max of dabigatran by 2.38-fold and 2.35-fold, respectively, after a single oral dose of 400 mg, and by 2.53-fold and 2.49-fold, respectively, after multiple oral doses of 400 mg once daily.

Dronedarone. When dabigatran etexilate is used concomitantly with dronedarone, total AUC_0–∞ and C_max of dabigatran increase by approximately 2.4-fold and 2.3-fold, respectively, after multiple doses of 400 mg dronedarone twice daily, and by approximately 2.1-fold and 1.9-fold, respectively, after a single 400 mg dose.

Itraconazole and cyclosporine. Based on in vitro data, effects similar to those observed with ketoconazole are expected.

Glecaprevir/pibrentasvir. Concomitant use of dabigatran etexilate with the fixed-dose combination of P-gp inhibitors glecaprevir/pibrentasvir increases the exposure to dabigatran and may increase the risk of bleeding.

Concomitant use not recommended

Tacrolimus. In vitro studies have shown that tacrolimus has a similar inhibitory effect on P-gp as itraconazole and cyclosporine. Clinical studies with dabigatran etexilate and tacrolimus have not been conducted. However, limited clinical data from use with another P-gp substrate (everolimus) suggest that tacrolimus inhibition of P-gp is weaker than that of strong P-gp inhibitors.

Caution required with concomitant use (see sections "Special warnings and precautions for use" and "Dosage and administration")

Verapamil. When dabigatran etexilate (150 mg) is used concomitantly with oral verapamil, C_max and AUC of dabigatran increase depending on the timing of administration and the formulation of verapamil (see sections "Special warnings and precautions for use" and "Dosage and administration").

The greatest increase in dabigatran exposure occurs when immediate-release verapamil is administered one hour before dabigatran etexilate (C_max increases approximately 2.8-fold and AUC approximately 2.5-fold). The effect gradually decreases with extended-release verapamil (C_max increases approximately 1.9-fold and AUC approximately 1.7-fold) or with multiple doses of verapamil (C_max increases approximately 1.6-fold and AUC approximately 1.5-fold).

No significant interaction was observed when verapamil was administered two hours after dabigatran etexilate (C_max increases approximately 1.1-fold and AUC approximately 1.2-fold). This is explained by complete absorption of dabigatran within two hours.

Amiodarone. When dabigatran etexilate is used concomitantly with a single 600 mg dose of amiodarone, the extent and rate of absorption of amiodarone and its active metabolite desethylamiodarone (DEA) are not significantly altered. AUC and C_max of dabigatran increase by approximately 1.6-fold and 1.5-fold, respectively. Due to the long elimination half-life of amiodarone, potential for interaction may persist for several weeks after discontinuation of amiodarone (see sections "Special warnings and precautions for use" and "Dosage and administration").

Quinidine. Quinidine was administered at 200 mg every 2 hours to a total dose of 1000 mg. Dabigatran etexilate was administered twice daily for 3 days, on day 3 with or without quinidine. AUC_τ,ss and C_max,ss of dabigatran increased overall by 1.53-fold and 1.56-fold, respectively, when quinidine was co-administered (see sections "Special warnings and precautions for use" and "Dosage and administration").

Clarithromycin. When clarithromycin (500 mg twice daily) was co-administered with dabigatran etexilate in healthy volunteers, AUC increased by approximately 1.19-fold and C_max by approximately 1.15-fold.

Tickagrelor. When a single dose of dabigatran etexilate 75 mg was co-administered with the highest initial dose of ticagrelor 180 mg, AUC and C_max of dabigatran increased by 1.73-fold and 1.95-fold, respectively. After multiple doses of ticagrelor (90 mg twice daily), dabigatran exposure increased by 1.56-fold and 1.46-fold for AUC and C_max, respectively.

Concomitant administration of the highest initial dose of ticagrelor 180 mg and dabigatran etexilate 110 mg (at steady state) increases AUC and C_max of dabigatran by 1.49-fold and 1.65-fold, respectively, compared to dabigatran etexilate alone. When the highest initial dose of 180 mg ticagrelor was administered 2 hours after 110 mg dabigatran etexilate (at steady state), the increases in AUC_τ,ss and C_max,ss of dabigatran were reduced to 1.27-fold and 1.23-fold, respectively, compared to dabigatran etexilate alone. This staggered administration is recommended at the initiation of ticagrelor with the highest initial dose.

Concomitant administration of 90 mg ticagrelor twice daily (maintenance dose) with 110 mg dabigatran etexilate increases AUC_τ,ss and C_max,ss of dabigatran by 1.26-fold and 1.29-fold, respectively, compared to dabigatran etexilate alone.

Posaconazole. Posaconazole also moderately inhibits P-gp but has not been clinically studied; therefore, caution should be exercised when co-administering posaconazole with dabigatran etexilate.

P-gp inducers

Concomitant use should be avoided

Rifampicin, St. John’s wort (Hypericum perforatum), carbamazepine, or phenytoin. Concomitant use may reduce dabigatran concentrations.

Overdosing with rifampicin 600 mg once daily for 7 days reduces total C_max and overall exposure of dabigatran by 65.5% and 67%, respectively. The inductive effect diminishes, resulting in dabigatran exposure close to baseline by day 7 after discontinuation of rifampicin. No further increase in bioavailability was observed during the subsequent 7 days.

Protease inhibitors such as ritonavir

Concomitant use not recommended

Ritonavir and its combinations with other protease inhibitors. These agents affect P-gp (both as inhibitors and inducers). They have not been studied and are therefore not recommended for concomitant use with dabigatran etexilate.

P-gp substrate

Digoxin. In a study involving 24 healthy volunteers, co-administration of dabigatran etexilate and digoxin showed no changes in digoxin parameters or clinically significant changes in dabigatran disposition.

Anticoagulants and antiplatelet agents.

Medicinal products whose therapy has not been studied or for which experience is limited and which may increase bleeding risk when used concomitantly with dabigatran etexilate: anticoagulants such as UFH, low molecular weight heparins (LMWH) and heparin derivatives (fondaparinux, desirudin), thrombolytics and vitamin K antagonists, rivaroxaban and other oral anticoagulants (see section "Contraindications"), antiplatelet agents such as GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran, and sulfinpyrazone (see section "Special warnings and precautions for use").

According to limited data from the RE-LY study in patients with atrial fibrillation, concomitant use of other oral or parenteral anticoagulants with dabigatran etexilate or warfarin increases the incidence of major bleeding by approximately 2.5-fold, primarily during transition from one anticoagulant to another (see section "Contraindications"). Additionally, concomitant use of antiplatelet agents, acetylsalicylic acid (ASA), or clopidogrel approximately doubles the rate of major bleeding with both dabigatran etexilate and warfarin (see section "Special warnings and precautions for use").

UFH may be used at doses required to maintain patency of a central venous or arterial catheter or during catheter ablation for atrial fibrillation (see section "Contraindications").

Interaction with anticoagulants and antiplatelet agents

Non-steroidal anti-inflammatory drugs (NSAIDs). Short-term use of NSAIDs for perioperative analgesia was not associated with increased bleeding risk when used concomitantly with dabigatran etexilate. However, long-term use of NSAIDs with dabigatran etexilate or warfarin in the RE-LY study increased bleeding risk by approximately 50%.

Clopidogrel. In young healthy male volunteers, concomitant use of dabigatran etexilate and clopidogrel did not prolong capillary bleeding time compared to clopidogrel monotherapy. Furthermore, AUC_τ,ss and C_max,ss of dabigatran and its effect on platelet aggregation inhibition remained unchanged compared to combination therapy and corresponding monotherapy. When 300 mg or 600 mg of clopidogrel was administered, AUC_τ,ss and C_max,ss of dabigatran increased by approximately 30–40% (see section "Special warnings and precautions for use").

Acetylsalicylic acid. Study data indicate that concomitant use of ASA with dabigatran etexilate 150 mg twice daily may increase the risk of major bleeding from 12% to 18% or 24% (with ASA 81 mg or 325 mg, respectively) (see section "Special warnings and precautions for use").

Low molecular weight heparins. Concomitant use of low molecular weight heparins such as enoxaparin and dabigatran etexilate has not been studied. After switching from 3-day enoxaparin therapy (40 mg once daily) to dabigatran etexilate, administered 24 hours after the last enoxaparin dose, dabigatran exposure was slightly lower than with dabigatran etexilate alone (single dose 220 mg). Higher anti-FXa/FIIa activity was observed after dabigatran etexilate administration following enoxaparin pretreatment compared to dabigatran etexilate alone. This is due to residual enoxaparin effect and is not clinically significant. Pretreatment with enoxaparin did not affect other anticoagulant tests for dabigatran.

Other interactions

Concomitant use of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). SSRIs and SNRIs increase the risk of bleeding during the study across all treatment groups.

Substances affecting gastric pH

Pantoprazole. When dabigatran etexilate is co-administered with pantoprazole, a decrease in AUC of dabigatran by approximately 30% is observed. In clinical trials, pantoprazole and other proton pump inhibitors (PPIs) were used concomitantly with dabigatran etexilate. Concomitant use of PPIs did not reduce the efficacy of dabigatran etexilate.

Ranitidine. Concomitant use of ranitidine and dabigatran etexilate had no clinically significant effect on the extent of dabigatran absorption.

Interactions related to the metabolic profile of dabigatran etexilate and dabigatran.

Dabigatran etexilate and dabigatran are not metabolized by the cytochrome P450 system and have no in vitro effect on cytochrome P450 enzymes. Therefore, interactions between dabigatran and corresponding medicinal products are not expected.

Special precautions.

Bleeding risk. Dabigatran etexilate should be used with caution in conditions associated with a high risk of bleeding or when used concomitantly with medicinal products affecting hemostasis by inhibiting platelet aggregation. Bleeding may occur at any site during treatment. If hemoglobin or hematocrit levels decrease for unknown reasons, or if arterial blood pressure drops, bleeding should be investigated.

In life-threatening or uncontrolled bleeding situations requiring rapid reversal of the anticoagulant effect, the specific reversal agent idarucizumab is available for administration. Dabigatran is dialyzable. The use of fresh whole blood, fresh frozen plasma, coagulation factor concentrates (activated or non-activated), recombinant factor VIIa, or platelet concentrates may be considered (see section "Overdose").

In clinical trials, dabigatran etexilate use was associated with a higher rate of major gastrointestinal bleeding. The risk was increased in elderly patients (≥75 years) receiving the 150 mg twice daily dose. Additional risk factors include concomitant use of antiplatelet agents such as clopidogrel and acetylsalicylic acid (ASA), or nonsteroidal anti-inflammatory drugs (NSAIDs), as well as the presence of esophagitis, gastritis, or gastroesophageal reflux.

Factors that may increase bleeding risk

Pharmacodynamic and pharmacokinetic factors: age ≥ 75 years.

Factors increasing plasma levels of dabigatran.
Significant: moderate renal impairment (CrCl 30–50 mL/min); strong P-gp inhibitors (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"); concomitant use of mild to moderate P-gp inhibitors such as amiodarone, verapamil, quinidine, and ticagrelor (see section "Interaction with other medicinal products and other forms of interaction").
Minor: low body weight (< 50 kg). Data in patients with body weight < 50 kg are limited (see section "Pharmacokinetics").

Pharmacodynamic interactions (see section "Interaction with other medicinal products and other forms of interaction"): ASA and other antiplatelet agents such as clopidogrel; NSAIDs; SSRIs or SNRIs; other medicinal products that may impair hemostasis.

Conditions/procedures associated with bleeding risk: congenital or acquired coagulation disorders; thrombocytopenia or platelet function defects; recent biopsy or major trauma; bacterial endocarditis; esophagitis, gastritis, or gastroesophageal reflux.

Preventive measures and bleeding risk management

For prevention of hemorrhagic complications, see section "Overdose".

Benefit-risk assessment. Injuries, conditions, procedures, and/or pharmacological therapies (e.g., NSAIDs, antiplatelet agents, SSRIs, SNRIs; see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction") that significantly increase the risk of major bleeding require careful benefit-risk evaluation. Dabigatran etexilate should be used only when the expected benefit outweighs the potential bleeding risk.

Close clinical monitoring. Close clinical monitoring for signs of bleeding or anemia is recommended throughout treatment, especially when multiple risk factors are present. Caution is advised when dabigatran etexilate is used concomitantly with verapamil, amiodarone, quinidine, or clarithromycin (P-gp inhibitors), particularly in patients with renal impairment (see section "Interaction with other medicinal products and other forms of interaction").

Close clinical monitoring for bleeding signs is recommended during concomitant treatment with NSAIDs (see section "Interaction with other medicinal products and other forms of interaction").

Discontinuation of dabigatran etexilate. Patients who develop acute renal failure should discontinue dabigatran etexilate (see section "Contraindications").

In cases of severe bleeding, treatment should be discontinued, the source of bleeding investigated, and the use of a specific reversal agent (idarucizumab) considered.

Dabigatran is eliminated by hemodialysis.

Use of PPIs. The use of proton pump inhibitors (PPIs) may be considered to prevent gastrointestinal bleeding.

Coagulation laboratory parameters. Although routine anticoagulant monitoring is generally not required with this medicinal product, assessing the anticoagulant effect related to dabigatran may be useful to identify excessively high dabigatran levels in the presence of additional risk factors.

Values of PT, aPTT, and TT may be very useful, but results should be interpreted cautiously due to differences between tests (see section "Pharmacodynamics").

The international normalized ratio (INR) test is unreliable in patients taking dabigatran etexilate, as false-positive INR elevation has been observed. Therefore, INR testing should not be performed.

Table 1 lists threshold values for coagulation tests that may be associated with an increased risk of bleeding (see section "Pharmacodynamics").

Table 1

Threshold values of coagulation tests that may be associated with an increased risk of bleeding

Use of fibrinolytic agents for the treatment of acute ischaemic stroke. Fibrinolytic agents may be considered for the treatment of acute ischaemic stroke if aPTT, PT or INR test results do not exceed the upper limit of normal (ULN) according to local reference ranges.

Surgery and invasive procedures. Patients receiving dabigatran etexilate who undergo surgical or invasive procedures are at increased risk of bleeding. Therefore, surgical intervention may require temporary discontinuation of dabigatran etexilate.

Patients may receive dabigatran etexilate during cardioversion. Data on the use of dabigatran etexilate 110 mg twice daily in patients with atrial fibrillation undergoing catheter ablation are lacking (see section "Dosage and administration").

Care should be taken when temporarily discontinuing treatment for surgery, and anticoagulation should be monitored. Dabigatran clearance may be prolonged in patients with renal impairment (see section "Pharmacokinetics"). Caution should be exercised with any procedure. In such cases, a coagulation test (see sections "Pharmacodynamics" and "Contraindications") may help determine whether haemostasis is impaired.

Emergency surgery or urgent procedures. Dabigatran etexilate should be temporarily discontinued. When rapid reversal of the anticoagulant effect is required, a specific reversal agent, idarucizumab, may be administered. Dabigatran is dialysable.

Reversal of dabigatran therapy may increase thrombotic risk in patients. Dabigatran etexilate may be restarted 24 hours after administration of idarucizumab, provided the patient is clinically stable and adequate haemostasis has been achieved.

Surgery and invasive procedures in subacute settings. Dabigatran etexilate should be temporarily discontinued. Surgical or invasive procedures should be delayed for at least 12 hours after the last dose of dabigatran, if possible. If surgery cannot be delayed, the risk of bleeding may be increased. The risk of bleeding and urgency of the procedure should be weighed before proceeding.

Planned surgery. If possible, dabigatran etexilate should be discontinued at least 24 hours prior to invasive or surgical procedures. For patients at increased risk of bleeding or undergoing major surgery where haemostasis may be required, discontinuation of dabigatran etexilate 2–4 days prior to surgery should be considered.

Table 2

Guidelines for discontinuation of treatment prior to invasive or surgical procedures

Spinal anesthesia/epidural anesthesia/lumbar puncture. Procedures such as spinal anesthesia may require full hemostatic function. The risk of spinal or epidural hematoma may be increased in cases of traumatic or repeated puncture and prolonged postoperative use of epidural catheters. After catheter removal, at least 2 hours should be waited before administering the first dose of dabigatran etexilate. Such patients require careful monitoring for neurological symptoms and signs of spinal or epidural hematoma.

Postoperative phase. Dabigatran etexilate therapy should be resumed/initiated after invasive procedures or surgery as soon as clinically appropriate and adequate hemostasis has been achieved.

Patients at risk of bleeding or patients at risk of excessive effect, especially those with reduced renal function, should be treated with caution (see sections "Pharmacodynamics" and "Contraindications").

Patients at high risk of mortality following surgery and with hereditary risk factors for thromboembolic complications. Data on the efficacy and safety of dabigatran etexilate in this patient group are limited; therefore, treatment should be administered with caution.

Surgery for hip fracture. There are no data on the use of dabigatran etexilate in patients who have undergone major orthopedic surgery for hip fracture; therefore, treatment is not recommended.

Hepatic impairment. Patients with elevated liver enzymes more than twice the ULN were excluded from the main clinical trials. Due to lack of experience, dabigatran etexilate is not recommended for this patient group. The use of the drug is contraindicated in patients with hepatic insufficiency or liver diseases that may affect survival (see section "Contraindications").

Interaction with P-gp inducers. Concomitant use of P-gp inducers is expected to reduce plasma levels of dabigatran; therefore, concomitant use with this group of medicinal products should be avoided (see sections "Pharmacokinetics" and "Interaction with other medicinal products and other forms of interaction").

Patients with antiphospholipid syndrome. Direct oral anticoagulants, including dabigatran etexilate, are not recommended for patients with a history of thrombosis and diagnosed antiphospholipid syndrome. In particular, in patients with triple positivity (lupus anticoagulant, anti-cardiolipin antibodies, and anti-beta-2-glycoprotein I antibodies), treatment with direct oral anticoagulants may be associated with an increased frequency of recurrent thrombotic events compared to vitamin K antagonist therapy.

Myocardial infarction. According to data from the RE-LY clinical trial (NVAF, see section "Pharmacodynamics") (dabigatran etexilate 110 mg twice daily, dabigatran etexilate 150 mg twice daily, and warfarin), the highest absolute risk of myocardial infarction was observed in the following subgroups with similar relative risk: patients with a history of myocardial infarction, patients aged ≥65 years with diabetes or coronary artery disease, patients with left ventricular ejection fraction <40%, and patients with moderate renal impairment. In addition, an increased risk of myocardial infarction was observed in patients receiving aspirin with clopidogrel or clopidogrel alone.

According to data from VTE/PE studies, a higher incidence rate of myocardial infarction was observed in patients treated with dabigatran etexilate compared to those treated with warfarin: 0.4% vs. 0.2% in short-term studies and 0.8% vs. 0.1% in long-term studies.

According to data from another study comparing dabigatran etexilate with placebo, the incidence rate of myocardial infarction was 0.1% in patients treated with dabigatran etexilate and 0.2% in patients receiving placebo.

Cancer patients (VTE/PE). The efficacy and safety of the medicinal product in this patient group have not been studied.

Special precautions for use. When removing a Dabifor® capsule from the blister pack, the following rules should be observed: separate one individual blister from the other blister along the perforated line; remove the hard capsule from the blister immediately before administration; peel off the foil without pushing the capsule through it.

Use during pregnancy or breastfeeding.

Women of reproductive potential. Women of reproductive potential should avoid pregnancy during treatment with Dabifor®.

Pregnancy. There are no adequate data on the use of Dabifor® in pregnant women. Animal studies have shown reproductive toxicity. The potential risk to pregnant women is unknown. Dabigatran etexilate should not be used during pregnancy except when the expected benefit to the woman outweighs the potential risk to the fetus.

Breastfeeding period. There are no clinical data on the effects of dabigatran on breastfed infants. As a precaution, breastfeeding should be discontinued.

Fertility. There are no data on the effect on fertility.

Ability to affect reaction speed when driving or operating machinery.

Dabigatran etexilate has no effect or a negligible effect on reaction speed when driving or operating machinery.

Method of Administration and Dosage.

Primary prevention of venous thromboembolism (VTE) in orthopedic surgery

The recommended doses of dabigatran etexilate and duration of treatment for primary prevention of VTE in orthopedic surgery are presented in Table 3.

Table 3

Recommended doses and duration of treatment for primary prevention of VTE in orthopedic surgery

*For patients with moderate renal impairment who are also taking verapamil (see "Special patient populations").

For both surgical procedures: if hemostasis at the wound surface area has not occurred, treatment initiation should be postponed. If treatment has not started on the day of surgery, it should be initiated with 2 capsules per day.

Assessment of renal function before and during dabigatran etexilate therapy

For all patients, especially elderly patients (> 75 years), as renal impairment may commonly occur in this age group:

• Before initiating dabigatran etexilate therapy, renal function should be assessed by calculating creatinine clearance to exclude patients with severe renal impairment (CrCl < 30 mL/min) (see sections "Pharmacokinetics", "Contraindications" and "Special precautions").
• Renal function should be assessed if there is suspicion of renal impairment during therapy (e.g., in cases of hypovolemia, dehydration, or concomitant use of certain medicinal products).

The method used to assess renal function (CrCl, mL/min) is the Cockcroft–Gault formula.

Missed dose. It is recommended to continue taking the daily dose of dabigatran etexilate at the usual time on the following day.

A double dose should not be taken to compensate for a missed dose.

Discontinuation of dabigatran etexilate. Dabigatran etexilate therapy must not be discontinued without consulting a physician. Patients should be advised to contact their physician if gastrointestinal symptoms such as dyspepsia occur (see section "Adverse reactions").

Switching from dabigatran etexilate to parenteral anticoagulant. It is recommended to wait 24 hours after the last dose of dabigatran etexilate before switching to a parenteral anticoagulant (see section "Interaction with other medicinal products and other forms of interaction").

Switching from parenteral anticoagulant therapy to dabigatran etexilate. Discontinue the parenteral anticoagulant and administer dabigatran etexilate 0–2 hours prior to the scheduled administration time of the alternative therapy or at the time of discontinuation, if continued treatment is required (e.g., intravenous unfractionated heparin (see section "Interaction with other medicinal products and other forms of interaction")).

Special patient populations

Patients with renal impairment. Dabigatran etexilate is contraindicated in patients with severe renal impairment (CrCl < 30 mL/min) (see section "Contraindications").

A reduced dose is recommended for patients with moderate renal impairment (CrCl 30–50 mL/min) (see Table 3 above and sections "Pharmacodynamics" and "Special precautions").

Concomitant use of dabigatran etexilate with mild to moderate P-gp inhibitors, such as amiodarone, quinidine, or verapamil. The dose of dabigatran etexilate should be reduced as specified in Table 3 (see also sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions"). In this case, dabigatran etexilate and the specified medicinal products should be administered at the same time.

For patients with moderate renal impairment who are taking verapamil, the dose of dabigatran etexilate should be reduced to 75 mg per day (see sections "Interaction with medicinal products and other forms of interaction" and "Special precautions").

Elderly patients. A reduced dose is recommended for elderly patients (> 75 years) (see Table 3 and sections "Pharmacodynamics" and "Special precautions").

Body weight. Clinical experience with the use of the medicinal product in patients with body weight < 50 kg or > 110 kg at the recommended dosage regimen is limited. Based on available clinical and pharmacokinetic data, dose adjustment is not required (see section "Pharmacokinetics"), but careful clinical monitoring is recommended (see section "Special precautions").

Gender. Dose adjustment is not required (see section "Pharmacokinetics").

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors (stroke prevention in NVAF).

Treatment of DVT and PE and prevention of recurrent DVT and PE in adults.

Table 4

Recommended doses for NVAF, DVT and PE

In the case of DVT/PE, 220 mg of dabigatran etexilate is recommended: 1 capsule of 110 mg twice daily. This dose is based on pharmacokinetic and pharmacodynamic analyses and has not been studied under clinical conditions.

See information provided below and sections "Pharmacodynamics", "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", and "Special precautions for use".

In case of intolerance to dabigatran etexilate, patients should be instructed to consult their physician immediately regarding switching to an alternative acceptable therapy to prevent stroke and systemic embolism associated with atrial fibrillation, as well as for the treatment of DVT/PE.

Assessment of renal function before and during treatment with dabigatran etexilate

In all patients, especially in elderly patients (>75 years), since renal impairment may frequently occur in this age group:

• Before initiating therapy with dabigatran etexilate, renal function should be assessed by calculating creatinine clearance to exclude severe renal impairment (CrCl < 30 mL/min) (see sections "Pharmacokinetics", "Contraindications", and "Special precautions for use").
• Renal function should be assessed if there is suspicion of impaired renal function during therapy (e.g., in cases of hypovolemia, dehydration, or concomitant use of certain medicinal products).

Additional requirements for patients with mild and moderate renal impairment and patients aged 75 years and older:

• During therapy with dabigatran etexilate, renal function should be assessed at least once a year or more frequently as needed in specific clinical situations where a decline or worsening of renal function is expected (e.g., in cases of hypovolemia, dehydration, or concomitant use of certain medicinal products).

The method used to assess renal function (CrCl, mL/min) is the Cockcroft-Gault formula.

Duration of treatment in NVAF, DVT, and PE

For NVAF, treatment with the medicinal product should be long-term.

For DVT and PE, the duration of treatment is determined individually after careful assessment of the benefit of treatment and bleeding risk (see section "Special precautions for use").

Short-term treatment (at least 3 months) should be based on transient risk factors (such as recent surgery, trauma, immobilization), and long-term treatment should be based on permanent risk factors or idiopathic DVT or PE.

Missed dose. A missed dose of dabigatran etexilate may be taken if there are at least 6 hours remaining before the scheduled time of the next dose. If less than 6 hours remain until the next dose, the missed dose should not be taken.

A double dose should not be used to compensate for a missed dose.

Discontinuation of dabigatran etexilate. Treatment with dabigatran etexilate should not be discontinued without medical consultation. Patients should be advised that if gastrointestinal symptoms such as dyspepsia occur, they should contact their physician (see section "Adverse reactions").

Switching from dabigatran etexilate to parenteral anticoagulant. It is recommended to wait 12 hours after the last dose before switching from dabigatran etexilate to a parenteral anticoagulant (see section "Interaction with other medicinal products and other forms of interaction").

Switching from parenteral anticoagulants to dabigatran etexilate. After discontinuation of parenteral anticoagulant therapy, dabigatran etexilate should be initiated 0–2 hours before the expected time of the next dose of parenteral anticoagulant or at the time of discontinuation of parenteral anticoagulant therapy during continuous treatment (e.g., intravenous UFH) (see section "Interaction with other medicinal products and other forms of interaction").

Switching from dabigatran etexilate to vitamin K antagonists. Transition conditions to vitamin K antagonists based on CrCl:

• CrCl ≥ 50 mL/min: initiation of vitamin K antagonists 3 days before discontinuation of dabigatran etexilate;
• CrCl ≥ 30 to <50 mL/min: initiation of vitamin K antagonists 2 days before discontinuation of dabigatran etexilate.

Since dabigatran etexilate may increase INR, INR will better reflect the effect of vitamin K antagonists only 2 days after discontinuation of dabigatran etexilate. Until then, INR values should be interpreted with caution.

Switching from vitamin K antagonists to dabigatran etexilate. Vitamin K antagonists should be discontinued. Dabigatran etexilate may be administered once the INR is < 2.0.

Cardioversion. Patients may take dabigatran etexilate during cardioversion.

Catheter ablation for atrial fibrillation (prevention of NVAF). Data on the use of dabigatran etexilate 110 mg twice daily in patients undergoing catheter ablation are lacking.

Percutaneous coronary intervention (PCI) with stenting (NVAF). Patients with NVAF who have undergone PCI with stenting may be treated with dabigatran etexilate in combination with antiplatelet agents after achieving hemostasis (see section "Pharmacodynamics").

Special patient groups

Elderly patients. For dosage recommendations specific to this patient category, see Table 4.

Patients at risk of bleeding. Patients at increased risk of bleeding (see sections "Pharmacological properties", "Interaction with other medicinal products and other forms of interaction", and "Special precautions for use") should be closely monitored clinically (for signs of bleeding or anemia). Individual dose adjustment may be considered at the physician’s discretion after evaluating potential benefits and risks for each patient (see Table 4). A coagulation test (see section "Special precautions for use") may help identify patients at increased risk of bleeding due to excessive exposure to dabigatran. If excessive dabigatran exposure is detected in patients at high risk of bleeding, a reduced dose of 220 mg: 1 capsule of 110 mg twice daily is recommended. In the event of clinically significant bleeding, treatment should be discontinued.

Patients with gastritis, esophagitis, or gastroesophageal reflux disease may be considered for dose reduction due to increased risk of major gastrointestinal bleeding (see Table 4 and section "Special precautions for use").

Renal impairment. Treatment with dabigatran etexilate is contraindicated in patients with severe renal impairment (CrCl < 30 mL/min) (see section "Contraindications").

No dose adjustment is required for patients with mild renal impairment (CrCl 50–≤80 mL/min). For patients with moderate renal impairment (CrCl 30–50 mL/min), the recommended dose of dabigatran etexilate is 300 mg: 1 capsule of 150 mg twice daily. However, for patients at high risk of bleeding, the dose of dabigatran etexilate may be reduced to 220 mg: 1 capsule of 110 mg twice daily (see sections "Pharmacokinetics" and "Special precautions for use"). Close clinical monitoring is recommended for patients with renal impairment.

Concomitant use of dabigatran etexilate with mild to moderate P-gp inhibitors, e.g., amiodarone, quinidine, or verapamil. Dose adjustment is not required when used concomitantly with amiodarone or quinidine (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", and "Special precautions for use").

For patients receiving verapamil concomitantly, dose reduction is recommended (see Table 4 and sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use"). In this case, dabigatran etexilate and verapamil should be administered at the same time.

Body weight. Dose adjustment is not required (see section "Pharmacokinetics"), but careful clinical monitoring is recommended for patients with body weight < 50 kg (see section "Special precautions for use").

Gender. Dose adjustment is not required (see section "Pharmacokinetics").

Route of administration. Dabifor® capsules may be taken independently of food intake. The capsule should be swallowed whole with a glass of water to facilitate passage into the stomach. Patients should be advised not to open the capsule, as this may increase the risk of bleeding (see section "Pharmacokinetics").

Children.

There is no justification for the use of Dabifor® capsules in children for the following indications:

• Prevention of venous thromboembolic complications in patients who have undergone major orthopedic surgery of the hip or knee;
• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation;
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE).

Overdose.

Doses of dabigatran etexilate exceeding the recommended doses lead to an increased risk of bleeding.

In case of suspected overdose, a coagulation test may be used to assess bleeding risk (see sections "Pharmacological properties" and "Special precautions for use"). Calibrated quantitative aPTT or repeated aPTT measurements can help predict when specific dabigatran levels will be reached (see section "Pharmacological properties"); dialysis may also be initiated as an additional measure.

Excessive anticoagulation may require discontinuation of dabigatran etexilate treatment. Since dabigatran is primarily eliminated via the kidneys, adequate diuresis should be maintained.

Due to low plasma protein binding, dabigatran may be removed by dialysis; however, clinical experience with dialysis is limited (see section "Pharmacokinetics").

Management of bleeding complications

In the event of bleeding complications, treatment should be discontinued and the source of bleeding identified. Appropriate management should be considered depending on the clinical situation, e.g., surgical hemostasis or restoration of circulating blood volume, as directed by the physician.

In life-threatening situations or uncontrolled bleeding where rapid reversal of the anticoagulant effect of dabigatran is required, a specific reversal agent (idarucizumab) with antagonistic effect on the pharmacodynamic action of dabigatran may be administered (see section "Special precautions for use").

The use of coagulation factor concentrates (activated or non-activated) may be considered. There are some experimental data on the role of these agents in reversing the anticoagulant effect of dabigatran, but data on their clinical benefit and potential risk of recurrence of thromboembolic events are very limited. Coagulation tests may become unreliable after administration of the proposed coagulation factor concentrates. Caution should be exercised when interpreting these tests. Caution should also be exercised when using platelet concentrates in cases of thrombocytopenia or prolonged use of antiplatelet medicinal products. Symptomatic treatment should be administered as directed by the physician.

Expert consultation in coagulation may be considered in cases of significant bleeding (if such an expert is available).

Adverse Reactions

Summary of Safety Profile

The safety of dabigatran etexilate has been evaluated in clinical trials involving approximately 64,000 patients, of whom approximately 35,000 received treatment with dabigatran etexilate.

Overall, adverse reactions were observed in 9% of patients who underwent major orthopedic surgery for hip or knee replacement (short-term treatment up to 42 days), in 22% of patients with atrial fibrillation treated for stroke and systemic embolism prevention (long-term treatment over 3 years), in 14% of patients treated for DVT/PE, and in 15% of patients treated for prevention of DVT and PE.

The most common adverse reaction was bleeding, observed in approximately 14% of patients receiving short-term treatment following hip or knee replacement surgery, in 16.6% of patients with atrial fibrillation receiving long-term treatment for prevention of stroke and systemic embolism, and in 14.4% of patients treated for DVT/PE.

Since the patient populations treated for the three indications are not comparable and bleeding events are categorized by organ systems, a brief description of major and any bleeding events is separated by indication and presented in Tables 6–10.

Although the incidence was low during clinical studies, major or severe bleeding can occur and, depending on the location, may lead to loss of function, be life-threatening, or even result in fatal outcomes.

Table 5 lists adverse reactions identified during studies and from post-marketing data for the indications of primary prevention of venous thromboembolism following major orthopedic surgery for hip or knee replacement, prevention of stroke and systemic embolism in patients with atrial fibrillation, and treatment and prevention of deep vein thrombosis and pulmonary embolism, classified by system organ class and frequency. Frequency categories are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from available data).

Description of selected adverse reactions

Bleeding

Due to its pharmacological mechanism of action, the use of dabigatran etexilate may be associated with an increased risk of occult or overt bleeding, which can occur in any tissue or organ. The symptoms and severity (including fatal outcomes) depend on the location, extent, or spread of the bleeding and/or anemia. During clinical trials, mucosal bleeding (e.g., gastrointestinal, genitourinary) was observed more frequently with prolonged treatment with dabigatran etexilate compared to treatment with vitamin K antagonists. Therefore, in addition to adequate clinical monitoring, laboratory testing for hemoglobin/hematocrit levels is important for detecting occult bleeding. The risk of bleeding may increase in certain patient groups, such as patients with moderate renal impairment and/or those receiving concomitant therapy affecting hemostasis, or strong P-gp inhibitors (see section "Special precautions for use" ("Risk of bleeding")). Hemorrhagic complications may present as weakness, pallor, dizziness, headache, unexplained swelling, dyspnea, or unexplained shock.

Known bleeding complications, such as compartment syndrome, acute kidney injury due to hypoperfusion, and anticoagulant-related nephropathy, have been reported in patients with predisposing risk factors during treatment with dabigatran etexilate. Therefore, the likelihood of bleeding should always be considered when evaluating any patient receiving anticoagulant therapy. A specific reversal agent for dabigatran, idarucizumab, is available and can be used in cases of uncontrolled bleeding (see section "Overdose").

Primary prevention of VTE in orthopedic surgery

Table 6 presents data on the number (%) of patients participating in two pivotal studies on the prevention of venous thromboembolism.

Table 6

Prevention of stroke and systemic embolism in adult patients with atrial fibrillation with one or more risk factors.

Table 7 presents data on bleeding events ranging from major to any bleeding observed during the pivotal studies on stroke and systemic embolism prevention in patients with atrial fibrillation.

Table 7

The clinical benefits of dabigatran etexilate in preventing stroke and systemic embolism, as well as the reduced risk of intracranial bleeding compared to warfarin, have been observed in individual subgroups, for example according to renal impairment, age, and concomitant use of other medicinal products such as antiplatelet agents or P-gp inhibitors. A certain subgroup of patients has an increased risk of major bleeding when using anticoagulants; therefore, the excess bleeding risk with dabigatran may be due to gastrointestinal bleeding, typically occurring within 3–6 months after initiation of dabigatran etexilate therapy.

Treatment of DVT and PE and prevention of recurrent DVT and PE in adults (treatment of DVT/PE)

Table 8 presents data on bleeding events observed during the pooled pivotal studies on treatment of DVT/PE. In the pooled studies, the primary safety endpoints of major bleeding, major or clinically relevant non-major bleeding, and any bleeding were significantly lower compared to warfarin at the nominal alpha level of 5%.

Table 8

Bleeding events for both treatment methods were assessed after the first administration of dabigatran etexilate or warfarin following the end of parenteral therapy (oral treatment period only). It includes all bleeding events observed during dabigatran etexilate administration. For warfarin, all bleeding events were included except those observed during the transition period from parenteral therapy to warfarin.

Table 9 presents data on bleeding events observed during the combined main studies for VTE/PE prevention. Some bleeding events were significantly lower compared to those with warfarin at the nominal alpha level of 5%.

Table 9

* Risk ratio was not assessed, as no events were observed in either patient group.

Table 10 presents data on bleeding events observed during the main study on prevention of VTE/PE. The rate of combined major bleeding / clinically significant bleeding, as well as the rate of any bleeding at the nominal alpha level of 5%, was significantly lower in patients receiving placebo compared to those treated with dabigatran etexilate.

Table 10

Bleeding events in the RE-SONATE study aimed at prevention of VTE and PE

*Risk ratio was not estimated because no cases were identified in either patient group.

Agranulocytosis and neutropenia

Agranulocytosis and neutropenia have been reported very rarely during treatment with dabigatran etexilate. As adverse reactions were reported during post-marketing surveillance in a population of unknown size, the exact frequency cannot be reliably determined. The reporting rate was estimated to be 7 events per 1 million patient-years for agranulocytosis and 5 events per 1 million patient-years for neutropenia.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are obliged to report any suspected adverse reactions in accordance with applicable legislation.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. No special storage conditions required. Keep out of reach and sight of children.

Packaging. 10 capsules in blisters. 6 blisters in a carton.

Prescription status. Prescription only.

Manufacturer.

Batch control, release of the medicinal product

Towa Pharmaceutical Europe S.L., Spain.

Towa Pharmaceutical Europe S.L., Spain.

Batch control, release of the medicinal product

Pharmadox Healthcare Limited, Malta.

Pharmadox Healthcare Limited, Malta.

Manufacturer's name and address.

Calle De Sant Marti 75-97, Poligono Industrial Martorelles, Martorelles, 08107, Spain.

Calle De Sant Marti 75-97, Poligono Industrial Martorelles, Martorelles, 08107, Spain.

KW20A Kordin Industrial Park, Paola, PLA 3000, Malta.

KW20A Kordin Industrial Park, Paola, PLA 3000, Malta.

Marketing Authorization Holder. JSC "Farmak".

Address of the Marketing Authorization Holder. 63, Kyrylivska Street, Kyiv, 04080, Ukraine.